Thesis (Ph.D.)--University of Adelaide, Dept. of Molecular Biosciences, 2001? / Copy of author's previously published work inserted. Includes bibliographical references (leaves 160-182).

Thesis (Ph.D.)--University of Adelaide, Dept. of Biochemistry, 2001. / Bibliography: leaves 139-165.

Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2005? / "October 2004" Includes bibliographical references (leaves 201-256).

Thesis (Ph. D.)--Northeastern University, 2008. / Title from title page (viewed April 2, 2009). Graduate School of Arts and Sciences, Dept. of Chemistry and Chemical Biology. Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2008. / Title from first page of PDF file. Includes bibliographical references (p. 114-127).

Thesis (M. Phil.)--University of Hong Kong, 1999. / Includes bibliographical references (leaves 75-82).

Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2006. / Includes bibliographical references (leaves 96-103). Also available in electronic version.

Thesis (Ph.D.) - University of Queensland, 2005. / Includes bibliography.

Quinolinate phosphoribosyltransferase (QPRTase, E.C. 2.4.2.19) is considered to be a unique enzyme in that it is thought to catalyse two distinct chemical reactions. Both the transfer of a phosphoribosyl group from 5-phosphoribosyl-1- pyrophosphate onto the nitrogen of quinolinic acid and the subsequent decarboxylation of the intermediate to form nicotinic acid mononucleotide are thought to be catalysed by the QPRTase system. Analogues of quinolinic acid were designed as potential inhibitors of QPRTase. These contain acidic groups at the 2- and 3- positions but are unable to decarboxylate. However, such compounds may be able to undergo the phosphoribosyl transfer reaction, potentially increasing their inhibitory potency. These compounds may be useful as "biological tools" allowing the neurological effects of an increase in quinolinic acid levels to be investigated. The compounds may show anti-fungal activity blocking the kynurenine pathway for NAD production. 2-Sulfonicotinic acid was synthesised by the oxidation of 2-mercaptonicotinic acid by either basic potassium permanganate, or iodine, with the structure was confirmed by X-ray crystallography. In biological testing the acid was shown to be neither an agonist nor antagonist of the NMDA receptor, or to be neurotoxic. A number of synthetic routes towards 2-phosphononicotinic acid, an alternative quinolinic acid analogue, were attempted though none were successful. These included orthometallation strategies and palladium coupling reactions to incorporate the phosphonic acid group at the 2- position. Nucleophilic addition routes, methods of building up the pyridine ring and including non-selective phosphonic acid addition were also examined. However, a related derivative, 2-(phosphonomethyl)nicotinic acid, was successfully synthesised. The non-enzymic decarboxylation of N-alkyl quinolinic acids was investigated, for comparison with the decarboxylation reaction catalysed by QPRTase. Both N- methyl and N-ethylquinolinic acid were synthesised, and the pH versus rate profiles measured. The rate maximum for both compounds was at pH 1.5, with the rate decreasing both above and below the maximum. N-Methylquinolinic acid was 10 times faster than quinolinic acid itself, demonstrating the effect of the nitrogen substituent. The N-ethyl derivative decarboxylated a further 1.5 times faster, showing the effect of increasing the size of the substituent. An Arrhenius plot was also carried out, giving an activation energy for the reaction of 153 kJ mol-1. Attempts to prepare the N-propyl derivative were unsuccessful, as decarboxylation occurred very readily to give N- propylnicotinic acid.

Des études cliniques indiquent que l’hétérogénéité des récepteurs tyrosine kinase (RTK) dérégulés dans le cancer colorectal (CCR) contribue à la résistance aux thérapies ciblant qu’un seul RTK. Une alternative serait de cibler les protéines effectrices engagées par plusieurs RTK régissant les processus clés à la progression du CCR, mais la signalisation des RTK dans le CCR reste peu définie. Des travaux réalisés au laboratoire ont démontré par une approche dominante négative que le pouvoir oncogénique du RTK Met chez les cellules épithéliales intestinales transformées par une forme active de Met (Tpr-Met-IEC-6) serait dépendant des protéines Gab (Grb2-associated binder). Cette approche reposait sur l’inhibition de l’interaction entres les protéines Gab et Met par l’expression du domaine de Gab1 renfermant un motif d’interaction indirect aux RTK, via la protéine Grb2, et le site de liaison direct, unique à Gab1, avec Met. Ainsi, cette approche ne permet pas de discerner les effets de Gab1 de ceux de Gab2 en aval de Met. L’objectif de cette présente étude était de définir les rôles qui sont propres à Gab1 et à Gab2, en aval de Met, dans les cellules Tpr-Met-IEC-6. Pour ce faire, nous avons évalué l’impact d’une modulation de l’expression de Gab1 et de Gab2, par une approche d’interférence à l’ARN et de surexpression, sur les caractéristiques oncogéniques de ces cellules. De façon surprenante, nous démontrons que Gab1 affecte positivement l’expression Tpr-Met, la transformation morphologique ainsi que la croissance cellulaire. De plus, nous démontrons que la diminution ou la surexpression de Gab2 dans les cellules Tpr-Met-IEC-6 n’a aucun effet sur la morphologie, la croissance cellulaire, la capacité des cellules à croître au-delà de la confluence et sans ancrage à la matrice extracellulaire et enfin sur la migration. En conclusion, mes travaux de recherche suggèrent que la protéine Gab1, et non Gab2, joue un rôle essentiel dans le pouvoir oncogénique de Met dans les cellules épithéliales intestinales. Ainsi, Gab1 et ses voies de signalisation pourraient représenter des cibles prometteuses pour l’élaboration de nouvelles thérapies contre le CCR.